PROJECT SUMMARY/ABSTRACT Excessive daytime sleepiness (EDS) is a very common symptom in the population, and has negative effects on health and well-being across the life span. Despite the importance of EDS, little is known about the biological changes in the brain associated with daytime somnolence, and objective measures currently used to quantify EDS have significant limitations. Of particular importance is that no current measure of sleepiness accounts for the multidimensional nature of the symptom itself, which is a significant barrier in the symptom science of EDS. This application is grounded in the fundamental philosophy that to understand the biological bases of excessive sleepiness requires that the phenotype itself be more carefully measured. The use of more precise objective sleepiness phenotypes will enhance the identification of persons with EDS, as well as the mapping of these phenotypes to specific brain circuits/pathways. Preliminary data suggest that identification of patients with EDS is dramatically enhanced using an approach that incorporates multiple measures of hypersomnolence. In addition, preliminary studies demonstrate that reduced slow wave activity in the supramarginal gyrus/somatosensory cortex during sleep and thalamostriatal functional connectivity during wake, are each associated with the subjective complaint of daytime sleepiness. Building on these data, the next crucial steps in the symptom science of daytime sleepiness are to 1) verify the importance of multimodal hypersomnolence assessments relative to healthy controls, and 2) to map these neurobiological findings to specific objective measures of daytime somnolence. Thus, this study will address three Specific Aims targeted towards these vital areas of inquiry in the symptom science of EDS. First, this investigation will verify whether a multimodal hypersomnolence assessment, that considers several facets of daytime sleepiness, identifies persons with unexplained EDS (n=31) compared to age- and sex-matched healthy controls (n=31). Second, it will identify specific objective measures of sleepiness that are associated with local reductions in slow wave activity during sleep in the supramarginal gyrus/somatosensory cortex in these study participants. Third, it will identify specific objective measures of sleepiness that are associated with reduced thalamostriatal functional connectivity during wake in these same research participants. These achievements will have a sizeable impact on the symptom science of daytime sleepiness, by enhancing the ability to objectively identify persons with daytime somnolence, as well as linking measurable sleepiness phenotypes to associated physiological processes in the brain. In so doing, this project will begin to dissect the various neurobiological pathways responsible for sleepiness as a symptom, a crucial step in developing personalized medicine approaches to the care of patients with chronic sleepiness through targeted interventions to improve outcomes.